PROJECT SUMMARY Alzheimer's disease (AD) is a prevalent neurodegenerative disorder that leads to cognitive decline and dementia. The disease imposes emotional and financial burdens on patients and their families, with over 5.8 million adults in the US alone affected by AD. The number of cases is expected to double by 2050, with estimated costs exceeding $1 trillion. Early diagnosis is crucial for effective management and prevention of AD, but current diagnostic methods like neuroimaging and cerebrospinal fluid analysis have limitations in terms of cost, availability, and invasiveness. Blood-based biomarkers offer a promising alternative for accessible and repeated measurements. Recent advancements in blood-based biomarkers, including amyloid-beta (Aβ), phosphorylated tau (pTau), and Neurofilament Light chain (NfL), show potential in diagnosing and tracking AD. Plasma Aβ levels can detect abnormalities before the onset of dementia symptoms, while elevated concentrations of specific pTau isoforms are strongly associated with clinically diagnosed AD. NfL serves as a broad indicator of neurodegeneration. These biomarkers align with findings from CSF and PET methodologies, presenting opportunities for transforming AD diagnosis, prognosis, and treatment monitoring. Despite the FDA approval of immunoassays for amyloid plaques and pTau, there is a significant lack of commercially available point-of-care (POC) blood tests for AD. Existing blood-based AD tests are lab-specific, bulky, expensive, and require specialized equipment. The EU/US Clinical Trials on Alzheimer's Disease (CTAD) Task Force emphasizes the urgent need for user-friendly, accurate, and accessible tests, particularly in primary care settings. Implementing POC testing alongside cognitive assessment could reduce specialist visits, shorten wait times, and generate significant cost savings for healthcare systems. To address these challenges, we propose to develop a smartphone-based POC diagnostic system. The system utilizes microfluidics, nanotechnology, optical sensing, and deep learning to detect AD-related biomarkers (Aβ42, Aβ40, pTau181, pTau217, pTau231, and ΝfL) in blood-plasma within 30 minutes. The goal is to create an affordable (<$5 material costs), disposable, and mass-producible microfluidic cartridge that enables rapid and sensitive (LoD<10pg/mL) detection using platinum nanoparticles to generate visible optical signal (bubbles). This innovation has the potential to fill the gap in AD management by providing an accessible and cost-effective tool for comprehensive blood-based biomarker testing, improving screening, monitoring, and treatment efficacy for individuals affected by AD.